PROJECT SUMMARY Arterial and venous thrombosis can cause ischemic injuries in a multitude of tissues. Occlusions can arise slowly from the progression of atherosclerotic disease or acutely due to thrombo-embolization. Serious clinical manifestations of thrombotic occlusions include myocardial infarction (MI), deep vein thrombosis (DVT), and pulmonary embolism (PE). Quickly restoring blood flow is critical for preventing death following thrombotic occlusions, however, reperfusion can result in scar tissue that limits subsequent tissue function. Examples include cardiac fibrosis following MI and post-thrombotic syndrome following DVT. Unfortunately, no effective strategies have been established to prevent fibrosis following thrombus resolution. The objective of this proposal is to develop a novel targeted dual therapeutic system for treatment of thrombotic occlusions that addresses the critical needs to reperfuse the blocked vessel and prevent subsequent fibrosis. We will achieve this by combining a fibrin-targeting particle platform with temporally controlled delivery of a fibrinolytic drug, which will restore blood flow to the ischemic tissue, followed by delivery of a small molecule Rho-associated kinase (ROCK) inhibitor, which will block key cellular responses involved in the onset and progression of fibrosis. This work is significant because it is the first treatment strategy to address the critical needs to quickly reperfuse tissue and treat subsequent fibrosis following thrombotic occlusions.